Pyrazolo[3,4-d]pyrimidines c-Src inhibitors reduce epidermal growth factor-induced migration in prostate cancer cells.

During its biol. progression, prostate cancer frequently develops dependence on growth factor receptors and their downstream signalling messengers, including c-Src. Evidence for this supports the choice of c-Src as a therapeutic target in the prevention of tumor spreading. Two new pyrazolo[3,4-d]pyrimidines c-Src inhibitors, SI35 and SI40, were used to investigate the role of c-Src in the control of the aggressive phenotype of prostate carcinoma cell line, PC3. SI mols. reduced the proliferation of PC3 cells in a time- and dose-dependent manner, with an IC50 of approx. 50 μM. PC3 cells responded to the presence of epidermal growth factor (EGF) by increasing their migratory ability, and this effect was strongly reduced by the addn. of SI at concns. less than IC50. Further observations demonstrated that SI mols. modulated cell morphol. and their adhesive capacity on different physiol. substrates. The action of SI mols. appeared to involve, in parallel with c-Src inhibition, the down-modulation of the active forms of paxillin and extracellular signal-regulated kinase (ERK). Our data suggest a promising role for pyrazolo[3,4-d]pyrimidines c-Src inhibitors in the control of a highly invasive tumor phenotype.